Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?

Abstract

The cytochrome P450 2D6 (CYP2D6) isoenzyme metabolizes about 25% of clinically used drugs. The impact of CYP2D6 metabolizer status on therapeutic outcome was assessed in 365 psychiatric in-patients treated with neuroleptics or antidepressants. Length of hospitalization and response onset were prolonged for patients receiving CYP2D6 drugs. Intermediate metabolizers (IMs) receiving CYP2D6 doses above the population median had more side effects after 4 weeks than extensive metabolizers with abovemedian doses (9/13, 69% vs 4/23, 17%, P ¼ 0.003), than IMs with belowmedian doses (5/22, 23%, P ¼ 0.012) and IMs with other medication (24/84, 29%, P ¼ 0.009). The Clinical Global Impression scale response was lower for IMs treated with CYP2D6 drugs (3/42, 7%) than for IMs with other medication (21/84, 25%, P ¼ 0.017) probably due to increased side effects. Identification of IM status (38% of study population) may help to reduce side effects and length/cost of hospitalization. Thus, not only poor and ultrarapid metabolizer but also IMs may benefit from CYP2D6 genotyping. This is of paramount interest since it greatly improves cost/benefit estimations for pretreatment CYP2D6 screening.

Serum Concentrations of Risperidone and Aripiprazole in Subgroups Encoding CYP2D6 Intermediate Metabolizer Phenotype

“…The sum of the CYP2D6 alleles is considered as the semiquantitative gene dose. This method classifies gene dose 0.5-1 (CYP2D6def/red, CYP2D6red/red, and CYP2D6*1/def) as IM phenotype as exemplified by Laika et al 31 and Steimer et al 32 However, based on the present and previous studies, collectively considering CYP2D6*1/def, CYP2D6red/red, and CYP2D6def/red genotypes as encoding IM phenotype can lead to loss of important phenotypical information within this group, as the former genotype clearly outnumbers the genotypes with 2 variant alleles. Therefore, in evaluating impact of CYP2D6 phenotype on pharmacokinetics and clinical effect, we suggest a separation of IMs in 2 groups: (1) genotypes with 1 fully functional and 1 nonfunctional variant allele and (2) genotypes with 2 variant alleles.…”

Fast Versus Slow Strategy of Switching Patients With Schizophrenia to Aripiprazole From Other Antipsychotics

“…25 Across the genetic variants of CYP2D6, the prescribed doses for poor metabolizers typically need to be 30% to 40% lower to achieve similar steady-state serum concentrations as ultrarapid metabolizers. 26 Similarly, agents that induce or inhibit CYP3A4 have been reported to increase or decrease aripiprazole clearance, 24 however, which that genetic variant of CYP3A4 can cause an increase or decrease in aripiprazole clearance is unclear.…”

Pharmacogenetics of Antipsychotics

“…24,33,34 Today, most evidence exists for an influence of CYP polymorphisms on motor adverse effects of APs, such as TD. Although some studies reported negative findings, [35][36][37][38] there is growing evidence that CYP2D6 PMs are at higher risk of developing acute EPSs 39,40 or TD [41][42][43] (see reviews 13,44,45 ). Some studies have also associated CYP1A2*1F with TD, 42,46 but other studies and a meta-analysis have yielded negative findings.…”